Wang et al. Infectious Agents and Cancer (2017) 12:47 DOI 10.1186/s13027-017-0153-6
RESEARCH ARTICLE
Open Access
Diagnostic value of prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) for early stage HBV related hepatocellular carcinoma Xiumei Wang1†, Weiwei Zhang1†, Youde Liu3, Wenjing Gong1, Ping Sun1, Xiangshuo Kong1, Miaomiao Yang1 and Zhihua Wang2*
Abstract Background: To evaluate the diagnostic efficacy of prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) for early stage hepatitis virus B (HBV) related hepatocellular carcinoma (HCC). Methods: Serums levels of PIVKA-II and a-Fetoprotein (AFP) was detected and compared in 113 patients with clinical confirmed Barcelona Clinic Liver Cancer (BCLC) stage 0-A HBV-related HCC and 161 chronic hepatitis B (CHB) patients. Diagnostic efficiencies as well as cut-off values of PIVKA-II, AFP and combination of the two markers were calculated using receiver operator curve (ROC) analysis. Results: The mean level of PIVKA-II among HCC patients were 79.64 ± 149.88, significantly higher than control group (P < 0.001). ROC results showed that among those AFP-negative HCC patients, the area under ROC curve (AUROC) of PIVKA-II was 0.73 (95%CI 0.640–0.815, P < 0.001). Among HCC patients diagnosed with small HCC (tumor size ≤2 cm), the AUROC of PIVKA- II was 0.692 (95%CI 0.597–0.788, P < 0.001). To evaluate the diagnostic value of PIVKA-II in HCC patient, all CHB cases were pooled together as control for analysis. The AUROC of PIVKA-II was 0.756 (95%CI 0.698–0. 814, P < 0.001), and the optimal cutoff value of PIVKA-II was 32.09 mAU/ml with sensitivity of 52.21% and specificity of 81.49%. When serum levels of PIVKA-II and AFP were combined to obtain a new marker for HCC diagnosis, PIVKAII + AFP further increased diagnostic efficiency, with AUROC of 0.868 (95%CI 0.822–0.913), higher than that of AFP (P < 0.01) or PIVKA-II (P < 0.001) alone. In addition, we found that HCC patients in poorly differentiated- undifferentiated group and in microvascular invasion group had higher levels of PIVKA-II. Multivariate analysis showed that high serum PIVKA-II level (OR = 1.003, 95%CI 1.001–1.007, P = 0.047) was an independent risk factor for microvascular invasion in HCC patients. Conclusion: Serum PIVKA-II level is a potential marker for early diagnosis of HCC and microvascular invasion. The use of PIVKA-II may improve assessment of tumor prognosis and guide development of therapeutic strategy. Keywords: Hepatocellular carcinoma, Hepatitis B virus, PIVKA-II, Early diagnosis
* Correspondence:
[email protected] † Equal contributors 2 Department of Gastroenterology, Yantai Yuhuangding Hospital, Yantai, Shandong 264000, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wang et al. Infectious Agents and Cancer (2017) 12:47
Background Hepatocellular carcinoma (HCC) ranks fifth in worldwide prevalence of malignant tumors and second in frequency of cancer related death. The general prognosis of patients with HCC is poor, which might be due to the late diagnosis of HCC. For the patients diagnosed at early stage of HCC, the 5-year survival rate is >70% [1]. Diagnosis of early stage HCC is heavily dependent on radiological imaging technique, which does not provide sufficient sensitivity. Biological markers in serum may facilitate the early diagnosis of HCC, thus improving survival rate. Currently, serum alpha-fetoprotein (AFP) level is the most commonly used biomarker for HCC. However, the sensitivity and specificity of diagnosis at early stage of HCC are still far from ideal [2]. There have been efforts in identification of new biomarkers for the early diagnosis of HCC. Various factors such as des-γcarboxyprothrombin, AFP-L3, glypican-3, osteopontin, Golgi protein-73 and a number of microRNAs have been suggested to be potential markers [1, 3]. Etiologies of HCC must be taken into consideration when choosing diagnostic biomarkers of HCC, since there are various pathological causes of HCC. It has been reported that chronic infection of hepatitis virus accounts for the majority of HCC development. However, the virus infection status varies significantly in different countries. Hepatitis B virus (HBV) infection has been shown to be mostly common in East Asia including China and HBV infection accounts for the major cause of HCC [4–6]. Approximately 240 million people worldwide are chronically infected with HBV and these people are at an increased risk of developing end-stage liver diseases, including cirrhosis and HCC [7–9]. Differential diagnosis of HBV related HCC patients and chronic HBV infected non-HCC patients is needed clinically. Therefore, the biomarkers have to reflect different pathological mechanisms of HBV infection [10]. Levels of prothrombin induced by vitamin K absenceII (PIVKA-II) have been identified to be elevated in HCC patients. Multiple studies have shown that PIVKAII has high sensitivity and specificity for diagnosis of HCC. Although PIVKA-II is mainly used as a diagnostic marker in Asia, studies in other populations, including Middle Eastern and European subjects, have also demonstrated its diagnostic value for HCC [11–13]. There has also been report that combination of PIVKA-II with other biomarkers may further increase the sensitivity and specificity for early diagnosis of HCC [14]. The PIVKA-II level has also recently drawn interest as a prognostic marker for HCC patients [15]. Despite of the relatively conclusive recognition of PIVKA-II as HCC biomarker, the specific diagnostic performance on HBV infection related HCC is still uncertain. For example, although it has been suggested that hepatitis virus infection had no apparent influence, commonly
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existed hyperbilirubinemia in HBV related hepatitis and liver cirrhosis may cause dysfunction of vitamin K absorption, resulting in different PIVKA-II level, which is different from hepatitis C virus infection. The current study aims to evaluate the performance of PIVKA-II, as well as PIVKA-II combined with AFP, in the diagnosis of HBV-related early stage of HCC.
Methods Study settings and patients
Enrolled subjected included patients administrated from January 2014 to March 2015 in Yantai Yu Huang top Hospital and Infectious Disease Hospital of Yantai City. Patients were allocated into two different categories: HBV-related HCC patients (HCC group) and chronic HBV infected non-HCC patients (CHB group). According to Barcelona Clinic Liver Cancer stage (BCLC), 38 patients in HCC group were at BCLC stage 0 and 75 patients were at BCLC stage A. BCLC stage 0 is defined as a single lesion ≤ 2 cm, and BCLC stage A is defined as single lesion between 2 and 5 cm or ≤3 lesions with each lesion ≤3 cm. In CHB group, there are two kinds of people: patients with cirrhosis and patients without cirrhosis. A Total of 113 subjects were included in HCC group and 161 subjects were included in CHB group. The baseline characteristics of the two groups of patients were listed in Table 1. The diagnosis of liver cancer was made in accordance with the standards of diagnosis and treatment of primary liver cancer (2011 Edition) issued by the Ministry of public health of the People’s Republic of China [16]. The diagnosis of Chronic hepatitis B infection and cirrhosis was in accordance with the revised guidelines for the prevention and treatment of chronic hepatitis B Table 1 Patient information and baseline characteristics Sample size
HCC
CHB
113
161
Gender
P value 0.435
Male
104
152
Female
9
9
Yes
80
102
No
33
59
48 (28–70)
50 (21–75)
0.237
ALT
74.02 ± 38.83
77.89 ± 84.87
0.650
AST
78.97 ± 46.59
69.64 ± 42.54
0.087
ALB
38.04 ± 10.97
40.36 ± 5.64
0.041
TBIL
27.13 ± 11.65
14.03 ± 7.57
